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Functional analysis ofAIRE, a gene responsible for the hereditary type of autoimmune disease

Research Project

Project/Area Number 17390291
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionThe University of Tokushima

Principal Investigator

MATSUMOTO Mitsuru  The University of Tokushima, Institute for Enzyme Research, Professor, 分子酵素学研究センター, 教授 (60221595)

Co-Investigator(Kenkyū-buntansha) KURODA Noriyuki  The University of Tokushima, Institute for Enzyme Research, Assistant Professor, 分子酵素学研究センター, 助手 (50359915)
OSHIKAWA Kiyotaka  The University of Tokushima, Institute for Enzyme Research, COE Investigator, 分子酵素学研究センター, COE研究員 (50380051)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2006: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2005: ¥7,700,000 (Direct Cost: ¥7,700,000)
KeywordsAIRE / autoimmune disease / self-tolerance / thymus / NOD mic
Research Abstract

Factors that determine the spectrum of target organs involved in autoimmune destruction are poorly understood. Although loss of function of autoimmune regulator (AIRE) in thymic epithelial cells is responsible for autoimmunity, the pathogenic roles of AIRE in regulating target-organ specificity remain elusive. In order to gain insight into this issue, we have established NOD mice, an animal model of type I diabetes caused by autoimmune attack against b-cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than β-cell islets were the major targets of autoimmune destruction in Aire-deficient NOD mice, and this alteration of intra-pancreatic target-organ specificity was associated with production of auto-Ab against pancreas-specific protein disulfide isomerase (PDIp), an antigen expressed predominantly by acinar cells. Consistent with this pathologic change, the animals were resistant to the development of diabetes. The results suggest that Aire is not only critical for the control of self-tolerance but is also a strong modifier of target-organ specificity through regulation of T-cell repertoire diversification. We also demonstrated that transcriptional expression of PDIp was retained in the Aire-deficient NOD thymus, further supporting the concept that Aire may regulate the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (15 results)

All 2007 2006 2005 Other

All Journal Article (15 results)

  • [Journal Article] Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from claudin-expressing cells.2007

    • Author(s)
      Hamazaki, Y., et al.
    • Journal Title

      Nature Immunology (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice.2006

    • Author(s)
      Niki, S., et al.
    • Journal Title

      Journal of Clinical Investigation 116

      Pages: 1292-1301

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Essential role of IκB kinase α in thymic organogenesis required for the establishment of self-tolerance.2006

    • Author(s)
      Kinoshita, D., et al.
    • Journal Title

      Jounal of Immunology 176

      Pages: 3995-4002

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] IκB kinase α is critical for Toll-like receptor 7- and 9-induced interferon α production.2006

    • Author(s)
      Hoshino, K., et al.
    • Journal Title

      Nature 440

      Pages: 949-953

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Essential role of IKB kinase a in thymic organogenesis required for the establishment of self-tolerance.2006

    • Author(s)
      Kinoshita, D., et al.
    • Journal Title

      J.Immunol. 176

      Pages: 3995-4002

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] IKB kinase a is critical for Toll-like receptor 7-and 9-induced interferon a production.2006

    • Author(s)
      Hoshino, K., et al.
    • Journal Title

      Nature 440

      Pages: 949-953

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice.2006

    • Author(s)
      Niki, S., et al.
    • Journal Title

      J.Clin.Invest. 116

      Pages: 1292-1301

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Essential role of IkB kinase a in thymic organogenesis required for the establishment of self-tolerance.2006

    • Author(s)
      Kinoshita, D., et al.
    • Journal Title

      Jounal of Immunology 176

      Pages: 3995-4002

    • Related Report
      2006 Annual Research Report
  • [Journal Article] IkB kinase a is critical for Toll-like receptor 7-and 9-induced interferon α production.2006

    • Author(s)
      Hoshino, K, et al.
    • Journal Title

      Nature 440

      Pages: 949-953

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Essential role of IκB kinase (IKK) α in thymic organogenesis required for the establishment of self-tolerance.2006

    • Author(s)
      Kinoshita D, et al.
    • Journal Title

      Journal of immunology (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] IκB kinase α is critical for Toll-like receptor 7- and 9-induced interferon α production.2006

    • Author(s)
      Hoshino K, et al.
    • Journal Title

      Nature (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.2005

    • Author(s)
      Kuroda, N., et al.
    • Journal Title

      J.Immunol. 174

      Pages: 1862-1870

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Dependence of self-tolerance on TRAF6-directed development of thymic stroma.2005

    • Author(s)
      Akiyama, T., et al.
    • Journal Title

      Science 308

      Pages: 248-251

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD-2 in antibody response to microbial membranes.2005

    • Author(s)
      Nagai, Y., et al.
    • Journal Title

      J.Immunol. 174

      Pages: 7043-7049

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from claudin-expressing cells.

    • Author(s)
      Hamazaki, Y., et al.
    • Journal Title

      Nature Immunol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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